Chemotherapy-induced peripheral neurotoxicity (CIPN) is a severe dose-limiting adverse event of chemotherapy. Presently, the mechanism underlying the induction of CIPN remains unclear, and no effective treatment is available. In this study, through metabolomics analyses, we found that nab-paclitaxel therapy markedly increased serum serotonin [5-hydroxtryptamine (5-HT)] levels in both cancer patients and mice compared to the respective controls. Furthermore, nab-paclitaxel-treated enterochromaffin (EC) cells showed increased 5-HT synthesis, and serotonin-treated Schwann cells showed damage, as indicated by the activation of CREB3L3/MMP3/FAS signaling. Venlafaxine, an inhibitor of serotonin and norepinephrine reuptake, was found to protect against nerve injury by suppressing the activation of CREB3L3/MMP3/FAS signaling in Schwann cells. Remarkably, venlafaxine was found to significantly alleviate nab-paclitaxel-induced CIPN in patients without affecting the clinical efficacy of chemotherapy. In summary, our study reveals that EC cell-derived 5-HT plays a critical role in nab-paclitaxel-related neurotoxic lesions, and venlafaxine co-administration represents a novel approach to treating chronic cumulative neurotoxicity commonly reported in nab-paclitaxel-based chemotherapy.
Paclitaxel/toxicity* ; Animals ; Albumins/adverse effects* ; Serotonin/metabolism* ; Mice ; Humans ; Male ; Female ; Venlafaxine Hydrochloride/therapeutic use* ; Neurotoxicity Syndromes/metabolism* ; Middle Aged ; Schwann Cells/metabolism* ; Peripheral Nervous System Diseases/drug therapy* ; Antineoplastic Agents

Ninety eight patients with chronic hepatitis B (CHB) admitted to Department of Infectious Diseases, Yongkang First People′s Hospital from January 2017 to June 2018 were randomly divided into two groups. On the basis of entecavir+dicyclool treatment, patients in control group (48 cases) received health education and weekly telephone follow-up from the nurses, while patients in intervention group (50 cases) received health guidance from doctors and psychological counseling and communication from the nurses. All patients were followed up for 8 weeks. The illness perception, negative emotions, quality of life, and medication compliance were evaluated with the Revised Illness Perception Questionnaire (IPQ-R), Self-rating Anxiety Scale (SAS), Self-rating Depression Scale (SDS), SF-36 and Morisky Medication Adherence Scale (MMAS-8) in two groups, respectively. The results showed that, after 8 weeks, the disease identity, serious consequences, treatment control and disease correlation; SAS and SDS scores; physiological function, emotional function, energy and social function were significantly improved in control group( t=2.30, 3.45, 2.35, 2.23, 5.04, 6.03, 2.03, 2.79, 2.02, 2.34, all P<0.05). All dimension of illness perception; SAS and SDS scores; physiological function, physiological function, emotional function, energy, mental health, social function and general health were also improved significantly in intervention group ( t=4.06, 5.44, 6.91, 8.53, 5.65, 8.77, 7.25, 6.06; 12.71, 11.91, 2.27, 2.60, 4.48, 2.82, 3.65, 3.461, 2.82,all P<0.05). And the personal control, disease correlation and emotional expression; SAS and SDS scores; emotional function and mental health in intervention group were better than those in control group ( t=1.49, 2.74, 2.60, 5.02, 5.18, 5.56, 13.72, all P<0.05). In addition, the medication compliance of patients in both groups was significant improved ( Z=5.56, 13.72, all P<0.01), and the improvement was more marked in the intervention group ( Z=3.22, P<0.01). The study indicates that the comprehensive psychotherapy can more significantly improve the degree of illness perception, negative emotions, quality of life and medication compliance in patients with chronic hepatitis B.